Lipid Absorption and Mobilization

1. Lipid Absorption and Mobilization

2. Lipoproteins • Transport water insoluble TAG, cholesterol and cholesterol-esters throughout circulatory system • Hydrophobic core containing TAG and cholesterol-esters • Hydrophillic surface made of proteins (apoproteins) and phospholipids)

3. Lipoproteins • Several different classes of lipoproteins. • Chylomicrons deliver dietary fats to tissues • VLDL, IDL and LDL transport endogenously synthesized TAG and cholesterol to tissues • HDLs remove cholesterol from serum and tissues and transports it back to the liver. • VLDL, IDL, LDL, and HDL named based on their density. Low density lipoproteins have high lipid to protein ratios. High density lipoproteins have low lipid to protein ratios.

6. Lipoproteins • Lipases in capillaries of adipose and muscle tissues degrade TAG in VLDLs. VLDLs become IDLs. • IDLs can then give up more lipid and become LDLs. • LDLs are rich in cholesterol and cholesterol-esters.

7. Apolipoproteins • VLDLs, IDLs, and LDLs all contain a large monomeric protein called ApoB-100. • ApoB-100 forms amphipathic crust on lipoprotein surface. • Chylomicrons contain analogous lipoprotein ApoB-48. • VLDLs and IDLs also possess a number of small weakly associated proteins that disassociate during lipoprotein degradation. • Small apolipoproteins function to modulate the activity of enzymes involved in lipid mobilization and interactions with cell surface receptors.

8. LDL Receptor • Binds to ApoB-100. • Found on cell surface of many cell types • Mediates delivery of cholestrol by inducing endocytosis and fusion with lysosomes. • Lysosomal lipases and proteases degrade the LDL. Cholesterol then incorporates into cell membranes or is stored as cholesterol-esters.

9. High LDL levels can lead to cardiovascular disease. • LDL can be oxidized to form oxLDL • oxLDL is taken up by immune cells called macrophages. • Macrophages become engorged to form foam cells. • Foam cells become trapped in the walls of blood vessels and contribute to the formation of atherosclerotic plaques. • Causes narrowing of the arteries which can lead to heart attacks.

10. Plaque Build up in Artery

11. Absence of LDL Receptor Leads to Hypercholesteremia and Antherosclerosis • Persons lacking the LDL receptor suffer from familial hypercholestermia • Result of a mutation in a single autosomal gene • Total plasma cholesterol and LDL levels are elevated. • Homozygous indivdiuals have cholesterol levels of 680 mg/dL. Heterozygous individuals = 300 mg/dL. Healthy person = <200 mg/dL. • Most homozygous individuals die of cardiovascular disease in childhood.

12. LDLs/HDLs and Cardiovascular Disease • LDL/HDL ratios are used as a diagnostic tool for signs of cardiovascular disease • LDL = “Bad Cholesterol” • HDL = “Good Cholesterol” • A good LDL/HDL ratio is 3.5 • Protective role of HDL not clear. • An esterase that breaks down oxidized lipids is associated with HDL. It is possible (but not proven) that this enzyme helps destroy oxLDL

13. Triacylglycerols are Highly Concentrated Energy Stores • Complete oxidation of fatty acids yield 9 kcal/gm while only 4 kcal/gm are generated from carbos and proteins. • Fatty acids are more reduced than proteins or carbos. • Since TAGs are non-polar and anhydrous (lacking hydration shell), can store more than 6 times as much energy per gm than glycogen.

14. Energy Reserves of a 150 lb Man • 100,000 kcal of TAG, 25,000 kcal protein, 600 kcal glycogen, 40 kcal glucose. • 24 lbs of body weight is TAG • Would need 121lbs of glycogen to store the same amount of energy

15. Absorption and Mobilization of TAG • Digestion of dietary lipids occurs in the small intestine. • TAG must be broken down to fatty acids for absorption across intestinal epithelium. • First TAG forms micelles with bile salts (amphipathic molecules drived from cholestrol) • The micelles form to orient ester bonds of TAG towards the hydrophillic surface to allow water soluble lipases to cleave molecule.

16. Bile Salt

17. Fatty acids and MAG enter mucosal cells where they are used to re-synthesize TAG • TAG is then packaged into lipoprotein transport particles called chylomicrons (lipoprotein). • Chylomicrons are mainly composed of TAG and apoprotein B-48. Also contain fat solubel vitamins • Chylomicrons enter the lymph system and then the blood stream. • Chylomicrons bind to membrane bound lipoprotein lipases at the surface of adipose and muscle cells.

18. Storage of FAT • TAG is delivered to adipose tissue in the form of chylomicrons and VLDLs. • The TAG is hydrolyzed and enters adipose cell as free fatty acid and MAG. • Fatty acids and MAG are re-esterified to form TAG. • TAG coalesce in the cytoplasm of adipose cells to form large globules

19. Mobilization of Fat • Epinephrine, noepinephrine, glucgon and adrenocorticotrophic hormones activate an adipose lipase. • The hormones bind to the 7M receptor on outer surface of the adipose cell plasma membrane. • Induces a G-protein mediated signal transduction pathway.

20. Mobilization of Fat • Free fatty acids are not soluble in blood plasma. • Fatty acids are carried through the blood stream on proteins called serum albumins. • Once fatty acids reach target cell it enters the cell and becomes esterified to CoA-SH and enters b-oxidation pathway • Glycerol generated from fat breakdown is absorbed by the liver it can serve as an intermediate for glycolysis or gluconeogenesis.